Project Summary/Abstract: The Melanoma Program (MEL) carries out impactful research aimed at improving patient outcomes by understanding melanoma biology and addressing unmet needs in melanoma management. This effort is facilitated by one of the nation?s oldest and largest biobanks of melanoma specimens, linked to prospective, and protocol-driven clinical information for more than 3,700 patients. Special areas of interest include: better stratification of recurrence risk after primary treatment, improved decision making for adjuvant treatment of those at high risk of recurrence, identification of the molecular drivers of melanoma progression with a particular focus on brain tropism, and developing new therapies for patients with advanced melanoma. Led by Iman Osman, MD and Jeffrey Weber, MD PhD, MEL comprises a multi-disciplinary team of 21 members representing 12 departments at NYU School of Medicine and other NYU colleges that advances basic science, translational and clinical melanoma research. Six new members filled strategic needs, and have advanced our goal of bringing novel therapeutics into the clinic. MEL has also significantly enhanced its research and outreach targeting the PCC catchment area with a new effort on acral melanoma, which disportionately affects African Americans and Hispanics. Since the last CCSG review, our NCI funding has nearly tripled from $729K to $2.1 million, while overall cancer-related funding has almost doubled from $3.4 to $6.03 million. Members published 354 papers, with 31% of the citations appearing in journals with IF>10. Members are highly collaborative: 19% of publications are intra-programmatic, 31% of publications are intra- programmatic, and 35% are inter-institutional (with NCI-CCs). During this funding period, MEL members made major strides in understanding the melanoma cell-of-origin and the mechanisms driving metastatic progression. We have focused our attention on downstream epigenetic and transcriptional programs, some that are directly ?druggable? (i.e., BRD4); others that indirectly result in emergence of novel targets (e.g., HSF1, AMIGO2, FUT8, PTK7). MEL co-leaders and several of its senior members recently submitted a SPORE application, which received a high impact score and will be resubmitted in May 2018. Our scientific goals are organized around three complementary thematic aims: Aim 1: To identify novel prognostic and predictive molecular biomarker(s) of melanoma progression and response to therapy, Aim 2: To understand the biologic heterogeneity of melanoma at the molecular level, and Aim 3: To develop new treatments that overcome therapeutic resistance. MEL promotes the PCC mission to improve cancer treatment, outcome, and quality of life for patients by: (1) accruing patients to high quality, investigator-initiated trials, (2) expanding a large melanoma biobank tied to clinical information, (3) pursuing science that informs patient stratification for personalized treatment, and (4) developing new approaches to detection, early intervention and treatment of advanced disease.